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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1423175
This article is part of the Research Topic New Drugs and Future Challenges in Drug Metabolism and Transport View all 7 articles
Preclinical Pharmacokinetic Studies and Prediction of Human PK profiles for Deg-AZM, a clinical-stage new Transgelin agonist
Provisionally accepted- 1 College of Pharmacy, Nankai University, Tianjin, China
- 2 The National Institutes of Pharmaceutical R&D Co., Ltd, Beijing, China
Deglycosylated azithromycin (Deg-AZM), a newly developed Class I drug with good therapeutic effects on slow transit constipation, is a small molecule Transgelin agonist which has been approved for clinical trials in 2024. The preclinical pharmacokinetic profile of Deg-AZM was investigated to support the further development for Deg-AZM. The results of plasma protein binding suggested that the plasma protein binding rates of Deg-AZM was lower in mice and rats, higher in dogs, and moderate in humans. By investigating the metabolic stability of liver microsome, it was found that the metabolic process of Deg AZM was similar in rat and human liver microsomes. Pharmacokinetic studies conducted on rats or dogs indicated no significant gender difference in the pharmacokinetic behavior of Deg-AZM. In addition, Deg-AZM was rapidly absorbed into the blood and then quickly eliminated from the body. Plasma exposure of Deg-AZM was dose-dependent with no accumulation after continuous gavage administration. Deg-AZM could widely distributed in the tissues without obvious accumulation. Deg-AZM was mainly excreted from the body through the urinary excretion pathway. Furthermore, the pharmacokinetic profiles in human of Deg-AZM at various doses were predicted based on physiologically-based pharmacokinetic (PBPK) models and we found the pharmacokinetic behavior of Deg-AZM showed dose-dependency. These results could provide valuable information to support the first in-human dosage prediction and phase I clinical design.
Keywords: 38 Tongyan Road, Jinnan District, Tianjin, P.R.China 300350 Deg-AZM, Nonclinical Pharmacokinetics, Absorption, Distribution, Metabolism, Excretion Deg-AZM, Deglycosylated azithromycin, LC-MS/MS, liquid chromatography coupled with tandem, ESI, electrospray ionization, MRM, multiple reaction monitoring, m/z, mass-to-charge ratio, IS, internal standard, QC, quality control, LLOQ, lower limit of quantification
Received: 25 Apr 2024; Accepted: 30 Jul 2024.
Copyright: © 2024 Ai, Gu, Li, Tian, Zheng, Cai, Xu, Zhao, Liu, Sun, Luo, Zhu, Zhou and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xiaoyu Ai, College of Pharmacy, Nankai University, Tianjin, China
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